As reported by Sutherland et al in "Cyclic AMP", Am. Rev. Biochem. 37, 149 (1968), cyclic adenosine monophosphate (C-AMP) has been established as an intracellular "second messenger", mediating many of the actions of a variety of different hormones. According to this theory, first messenger hormones, such as epinephrine and norepinephrine, influence adenyl cyclase contained at or within cell walls to form intracellularly cyclic AMP from adenosine triphosphate upon receipt of the extra-cellular hormone signal. The formed cyclic AMP in turn functions as a second messenger and stimulates intracellular functions particular to the target cells of the hormone. Cyclic AMP has thus been shown to "activate" protein kinases, which in turn produce physiological effects such as muscle contraction, glycogenolysis, steriodogenisis, and lipolysis.
Cyclic AMP is degraded, however, in vivo by phosphodiesterase enzymes, which catalyze hydrolysis of the cyclic purine nucleotide to 5'-adenosine monophosphate with a consequent loss of function. It has accordingly been suggested that substituted cyclic AMP analogs which are more resistant to phosphodiesterase degradation than the naturally occurring cyclic nucleotide might be administered in aid of lagging cellular processes. Synthetic production of such compounds, however, is quite costly. It would be advantageous, therefore, to enhance the beneficial effects of naturally produced cyclic AMP by administering compounds which are capable of inhibiting the undesirable effects of phosphodiesterase enzymes.
Sutherland et al, in Circulation 37, 279 (1968), suggest that the pharmacological effects of theophylline, which has the structure ##STR2## are the result of its ability to inhibit the action of phosphodiesterase enzymes. Theophylline has thus been employed in lieu of the adenyl cyclase-stimulating hormones, epinephrine and norepinephrine, as a heart stimulants following cardiac arrest and in refractory asthma cases as a bronchial dilator. Theophylline, however, does not selectively inhibit phosphodiesterase, but rather gives general stimulation to the central nevous system. Accordingly, the use of theophylline can make the recipient nervous and irritable and can also create cardiovascular effects, i.e., rapid beating. By the same token, theophylline is not as potent as a phosphodiesterase inhibitor as is desired and consequently has to be used in larger quantities, which, of course, can further the undesirable effects enumerated above.
F. L. Rose et al, in articles appearing in J. Chem. Soc. 5642 (1963), 3357 (1965), and 1593 (1969), reported a number of triazolo[2,3-c]-pyrimidines and triazolo[4,3-c]pyrazines (for example, compounds 1 and 2 shown below) which are structurally related to theophylline and capable of protecting animals from histamine-induced bronchospasm. ##STR3##
Based on the possibility that the pharmacological effects of compounds 1 and 2 may be the result of the same biochemical mechanism as proposed for theophylline, various 5,7-dialkyl-pyrazolo[1,5-a]pyrimidines were prepared and found to possess phosphodiesterase enzyme inhibitory capability, as set forth in our aforesaid application, Ser. No. 273,465. This accordingly led to the investigation of additional 3,5,7-substituted pyrazolo[1,5-a]pyrimidines.